Lung epithelial barrier function and wound healing are decreased by IL-4 and IL-13 and enhanced by IFN-gamma

Am J Physiol Cell Physiol. 2001 Dec;281(6):C2029-38. doi: 10.1152/ajpcell.2001.281.6.C2029.

Abstract

To understand the effects of cytokines on epithelial cells in asthma, we have investigated the effects of interleukin (IL)-4, IL-13, and interferon (IFN)-gamma on barrier function and wound healing in Calu-3 human lung epithelial cells. IL-4 and IL-13 treatment of Calu-3 cells grown on Transwell filters resulted in a 70-75% decrease in barrier function as assessed by electrophysiological and [(14)C]mannitol flux measurements. In contrast, IFN-gamma enhanced barrier function threefold using these same parameters. Cells treated concurrently with IFN-gamma and IL-4 or IL-13 showed an initial decline in barrier function that was reversed within 2 days, resulting in barrier levels comparable to control cells. Analysis of the tight junction-associated proteins ZO-1 and occludin showed that IL-4 and IL-13 significantly reduced ZO-1 expression and modestly decreased occludin expression compared with controls. IFN-gamma, quite unexpectedly given its enhancing effect on barrier function, reduced expression of ZO-1 and occludin to almost undetectable levels compared with controls. In wound-healing assays of cells grown on collagen I, IL-4 and IL-13 decreased migration, whereas IFN-gamma treatment enhanced migration, compared with control cells. Addition of IFN-gamma, in combination with IL-4 or IL-13, restored migration of cells to control levels. Migration differences observed between the various cytokine treatments was correlated with expression of the collagen I-binding alpha(2)beta(1)-integrin at the leading edge of cells at the wound front; alpha(2)beta(1)-integrin expression was decreased in IFN-gamma-treated cells compared with controls, whereas it was highest in IL-4- and IL-13-treated cells. These results demonstrate that IL-4 and IL-13 diminish the capacity of Calu-3 cells to maintain barrier function and repair wounds, whereas IFN-gamma promotes epithelial restitution by enhancing barrier function and wound healing.

MeSH terms

  • Asthma / immunology
  • Asthma / physiopathology
  • Biological Transport
  • Blood-Air Barrier / physiology*
  • Cadherins / metabolism
  • Cell Movement / physiology
  • Humans
  • Integrins / metabolism
  • Interferon-gamma / metabolism*
  • Interleukin-13 / pharmacology*
  • Interleukin-4 / pharmacology*
  • Lung / drug effects
  • Lung / physiology*
  • Mannitol / metabolism
  • Membrane Proteins / metabolism
  • Microscopy, Confocal
  • Occludin
  • Phosphoproteins / metabolism
  • Receptors, Collagen
  • Receptors, Interleukin-4 / metabolism
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / physiology*
  • Tumor Cells, Cultured
  • Wound Healing / physiology*
  • Zonula Occludens-1 Protein

Substances

  • Cadherins
  • Integrins
  • Interleukin-13
  • Membrane Proteins
  • OCLN protein, human
  • Occludin
  • Phosphoproteins
  • Receptors, Collagen
  • Receptors, Interleukin-4
  • TJP1 protein, human
  • Zonula Occludens-1 Protein
  • Interleukin-4
  • Mannitol
  • Interferon-gamma